Project Summary/Abstract The progressive accumulation of ?-synuclein intracellular inclusions in the nervous system is a characteristic feature of dementia with Lewy bodies and Parkinson's disease which are part of a spectrum of sporadic and hereditary neurodegenerative diseases termed ?-synucleinopathies. The definitive involvement of ?-synuclein in the etiology of these disorders was established by the findings that mutations in ?-synuclein can directly cause these neurodegenerative disorders. Many studies suggest that the progressive spread of ?-synuclein pathology in the peripheral nervous system and the brain through direct ?-synuclein interactions and transmission between cells may contribute to disease progression. However, some studies characterizing the properties of novel ?- synuclein mutants demonstrated divergent effects that are not consistent with this simple spreading mechanism. It is also important to emphasize that there is still ongoing debate as to the nature of the toxic ?-synuclein species. To provide new insights on these contentious and critical issues that will address the unique properties of disease-associated ?-synuclein mutants, we have formed a team of experienced investigators with diverse and unique expertise. In Aim 1, we will determine the inherent aggregation and neurotoxicity properties of these novel ?-synuclein mutants in vivo and compare these outcomes to the more extensively characterized ?-synuclein mutants. In Aim 2, we will test the hypothesis that in vivo prion-like seeding can differentially impact the induction and propagation of ?-synuclein inclusion pathology of disease-causal ?-synuclein mutants with unique stain-like properties. These studies will provide pivotal information regarding the neurotoxicity of abnormal forms of ?- synuclein, their impact of the induction and spread of ?-synuclein pathology and the associations with neurodegeneration.